tbuckley/cabot-search huggingface dataset:
NIMG-73. PREDICTING PERITUMORAL GLIOBLASTOMA INFILTRATION USING QUANTITATIVE MAGNETIC RESONANCE FINGERPRINTING RADIOMICS
Authors: Walter Zhao, Shengwen Deng, Yong Chen, Anahita Fathi Kazerooni, Christos Davatzikos, Marta Couce, Xiaofeng Wang, Andrew Sloan, Dan Ma, Chaitra Badve
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Standard clinical magnetic resonance (MR) imaging of glioblastoma (GB) cannot identify malignant infiltration into the peritumoral non-enhancing region. This work implements quantitative MR fingerprinting (MRF) based radiomics to predict infiltrative regions of GB. METHODS Pre-operative MRF T1 and T2 maps along with multiparametric MR (mpMR) images (T1w, T2w, T1w-Gd, FLAIR, and ADC) from GB patients (n = 10) were analyzed. All subjects had histologically confirmed sites of non-enhancing peritumoral infiltration as identified by intra-operative 5-ALA fluorescence-guided tissue resection. These locations (n = 40) were manually annotated on pre-operative FLAIR by a board-certified neuroradiologist and labeled as “infiltration” (INF). For each patient, another FLAIR region ( &amp;gt; 3 cm from the enhancing tumor margin) was identified and labeled as “edema” (ED). Following image co-registration, 693 handcrafted radiomic voxel-based features were extracted from confirmed infiltration (INF) and edema (ED) voxels using a 3D 5x5x5 voxel sliding kernel. Feature selection was performed using the minimum redundancy maximal relevance (MRMR) algorithm, then INF and ED voxel features were used to train two cross-validated binary support vector machine (SVM) models for voxel-wise infiltration prediction: 1) MRF only model and 2) combined MRF and mpMRI model. Following MRMR selection, the combined model included features from T1, T1w, T2w, T1w-Gd, FLAIR, and ADC images. Model performance was evaluated using one withheld subject with multiple known infiltration sites. Balanced test accuracy and receiver operating characteristic (ROC) curve analysis was used to evaluate classification performance. RESULTS The MRF only and combined model achieved balanced test accuracies of 77.87% and 73.21% and AUCs of 0.91 and 0.97, respectively. CONCLUSIONS This study demonstrates that MRF-based radiomic features can predict GB tumor infiltration with high accuracy and provide complementary value to standard clinical MRI features. Our results indicate the high potential of employing MRF to guide personalized GB treatment strategies.
EOLP-03. A RETROSPECTIVE STUDY ON CAUSE OF DEATH DUE TO HIGH-GRADE GLIOMAS IN PEDIATRIC VERSUS ADULT PATIENTS
Authors: Andrea Franson, Larry Junck, Samantha Lyons
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Limited literature exists on the presumed pathophysiologic mechanisms by which children, adolescents and adults die from high-grade gliomas (HGGs). This study aims to identify the likely specific cause of death in patients with HGG based on imaging review in proximity to death. A secondary aim is to assess the use and timing of palliative care/hospice in patients with HGG. We hypothesized that most patients with HGG, both adult and pediatric, die from primary neurologic failure as a result of local tumor progression, with additional causes including hydrocephalus with subsequent brainstem herniation or causes indirectly related to tumor progression such as systemic infection. METHODS We conducted a retrospective review of pediatric patients with WHO Grade 4 gliomas and adults with de novo Grade 3 or 4 gliomas or Grade 2 glial tumors that transformed to Grade 3/4, diagnosed from 2016 to 2021 at Michigan Medicine (IRB exemption obtained). We reviewed imaging and clinical records of patients who had brain MR and/or CT imaging within 3 - 6 weeks of death to determine a likely cause of death. RESULTS Twenty-six pediatric patients and 43 adult patients identified met inclusion criteria. Initial analysis reveals that the majority of patients with HGG died from local tumor progression and subsequent neurologic failure. We also noted a greater use of palliative care/hospice services in pediatric patients, with less frequent referral for adult patients at any time in their disease course. Pediatric patients are almost always supported by Child and Family Life, while psychological services are rarely received by adult patients. CONCLUSIONS Analysis is ongoing, though trends indicate that the primary cause of death in patients with HGG is through primary neurologic failure, and that there may be opportunities to lessen end-of-life suffering through patient education and the use of support services.
EXTH-48. INHIBITION OF SREBP-1 IS SYNTHETICALLY LETHAL WITH BCL-XL/BCL-2 INHIBITION IN GLIOBLASTOMA IN VITRO
Authors: Davide Tosin, Dominik Schlotter, Annika Hajosch, Michal Hlavac, Mike-Andrew Westhoff, Markus Siegelin, Christian Rainer Wirtz, Georg Karpel-Massler
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE A cellular homeostasis that is shifted away from apoptosis and a reprogramming of the lipid metabolism are both, features that are frequently encountered in glioblastoma. This study aimed at investigating whether interference with the lipid metabolism is synthetically lethal with inhibition of anti-apoptotic Bcl-2 family proteins in glioblastoma in vitro. METHODS Established (U251) and primary-cultured glioblastoma cells (PC38, PC40 and PC128) as well as glioblastoma stem-like cells (SC38 and SC40) were treated with the Bcl-xL/Bcl-2 inhibitor ABT-263 (navitoclax) and/or the SREBP-1 inhibitor Fatostatin. MTT-assays were performed to assess effects of the combination therapy on the cell viability. Isobolograms were calculated to characterize the drug-drug interaction. Spheroids were used to determine anti-proliferative effects in a 3-dimensional setting. Staining with annexin V/propidium iodide and flowcytometric analysis were performed to assess pro-apoptotic effects. For molecular analyses, Western blots and specific knock-down experiments with siRNA were performed. RESULTS Combined targeting of SREBP-1 and Bcl-xL/Bcl-2 led to a synergistic inhibitory effect on the cellular viability of established, primary-cultured and glioblastoma stem-like cells as well as spheroids. This effect was shown to be at least in part mediated by enhanced apoptosis and to occur in a caspase-dependent manner. On the molecular level, treatment with increasing concentrations of Fatostatin led to a downregulation of Mcl-1. CONCLUSION Our study indicates that combined inhibition of Bcl-xL/Bcl-2 and interference with the lipid metabolism targeting SREBP-1 synergistically induces caspase-dependent apoptosis in glioblastoma cells. This effect can also be observed in more complex 3-dimensional glioblastoma cell formations. Further studies will focus on deciphering the drug-induced alterations of the metabolic pathways that are responsible for the synergistic effect of this therapeutic strategy.
TMET-26. PRIMARY OLIGODENDROGLIOMA CELL CULTURE VIABILITY: AN IN VITRO STUDY WITH METABOLIC MODULATORS
Authors: Marcela Villaverde, Elsa Hincapié Arias, Martin Merenzon, Alejandro Mazzon, Eduardo Seoane, Denise Belgorosky, Ana Maria Eiján
Journal: Neuro-Oncology (2022)

Abstract Oligodendrogliomas are tumors that develop from oligodendrocytes, the myelinating cells of the central nervous system. Oligodendrocytes are highly metabolically active cells that synthesize and transfer metabolites to neighboring cells. Given its intimate metabolic relation with neurons, we aim to investigate oligodendrocyte metabolism as an antitumoral target. A recurred oligodendroglioma WHO grade III was surgically removed from a 50-year patient after 10 years of progression-free disease. The tumor sample was mechanically digested and cultured at 37oC, 5% CO2, in DMEM: F12, 10 % FBS and antibiotics. Primary oligodendroglioma cells were trypsinized and seeded in a 96-well plate. After 24 hs, cells were treated with metabolic modulators: metformin (MET, mitochondrial complex II inhibitor, 5 mM), 2 deoxyglucose (2DG, hexokinase inhibitor, 1 mM), 6-aminonicotinamide (6AN, pentose phosphate pathway inhibitor, 50 µM) and/or 1400W and S-methylisothiourea (both iNOS inhibitors, 5 µM, and 50 µM respectively). Standard treatment with temozolomide (TMZ, 200 µM) was also performed. After 5 days of treatment, cells were stained with violet crystal. Two weeks after tumor sample digestion, a primary oligodendroglioma culture was successfully established. In vitro, proliferating cells appeared mostly undifferentiated with reduced branching complexity. Hexokinase inhibition by 2DG notoriously affected the viability of oligodendroglioma cells. Similar results were obtained with standard TMZ treatment. On the other hand, the inhibition of the pentose phosphate pathway by 6AN did not affect the cell monolayer. However, 6AN was able to increase the effect of MET as monotherapy. Both, MET and 2DG altered oligodendrocyte morphology inducing a more fusiform shape. Finally, iNOS inhibition modestly disrupted cell's monolayers and this effect did not seem to be improved by combinatory therapies. Glycolytic inhibitor 2DG resulted effective against oligodendroglioma cells. Whereas further studies are needed to validate these results, a better understanding of metabolic susceptibility could allow the development of better-targeted and more-effective therapeutic approaches.
QLTI-24. ANALYSIS OF DISPARITIES IN PEDIATRIC BRAIN TUMOR BANK ENROLLMENT AS FOUNDATION FOR QUALITY IMPROVEMENT INITIATIVES AT DANA-FARBER CANCER INSTITUTE/BOSTON CHILDREN’S CANCER AND BLOOD DISORDERS CENTER
Authors: Mary Tabatneck, Puja Umaretiya, Cecilia Sousa, Jayne Vogelzang, Keith Ligon, Lissa Baird, Tabitha Cooney
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Tissue biobanks play a vital role in oncology research; however, disparities have been reported in enrollment. The representativeness of biobanks is an important consideration in the extrapolation of research to the broader population. We sought to identify associations between sociodemographic characteristics and pediatric brain tumor bank enrollment at Dana-Farber Cancer Institute and Boston Children’s Cancer and Blood Disorders Center (DFCI/BCCBDC) to identify opportunities for improving equitable and representative enrollment. METHODS We conducted a retrospective cohort study of all patients qualified for enrollment in DFCI/BCCBDC Integrated Tissue and Clinical Data Bank for Patients with Neurological Disorders from 2014-2017 and extracted sociodemographic information from the medical record. The primary outcome was biobank enrollment, and the secondary outcome was approach for enrollment among non-enrolled patients. Exposures of interest included sex, language, interpreter need, race, and ethnicity. RESULTS We identified 652 eligible patients of which 580 (89%) enrolled and 72 (11%) were non-enrolled. Non-enrolled patients were more likely to be non-English speaking compared to enrolled patients (20% vs 11%; p = 0.0019) and were more likely to require an interpreter (15% vs. 8%; p = 0.025). Non-enrolled patients were more likely to identify as non-white/other/multiple races compared to enrolled patients (29% and 17%; p = 0.0023). Sex and ethnicity were not associated with enrollment. Of the 72 non-enrolled patients, 19 (26%) were approached to discuss enrollment but declined consent. There were no sociodemographic differences between approached and not approached patients. CONCLUSION While overall enrollment rates in this single center pediatric brain tumor bank were high, non-English primary language, interpreter need, and non-white race were significantly associated with non-enrollment. There were no differences in terms of approach for enrollment, suggesting that opportunities to improve representation may include understanding the reasons for declining enrollment and improving the consent process for patients from historically marginalized groups.
CTIM-04. PHASE I STUDY OF IBRUTINIB WITH RADIATION AND TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Manmeet Ahluwalia, Neha Patel, Atulya Khosla, Yasmeen Rauf, Glen Stevens, Erin Murphy, Samuel Chao, Jennifer Yu, John Suh, David Peereboom
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Glioblastoma is associated with dismal outcomes with a survival of 15-18 months. A major challenge in glioblastoma is the inability to effectively target glioma stem cells (GSCs) that have the capacity for self-renewal. GSCs are resistant to radiation and traditional chemotherapy agents. Ibrutinib is a first-in-class, potent, small-molecule tyrosine kinase inhibitor of Bruton’s Tyrosine Kinase (BTK) and Bone marrow X-linked (BMX). BMX nonreceptor tyrosine kinase activates STAT3 signaling to maintain self-renewal and tumorigenic potential of GSCs. Hence a combination of ibrutinib with radiation and temozolomide in Glioblastoma is a promising approach. METHODS Unmethylated MGMT GBM patients received ibrutinib daily with 60 Gy radiation over 6 weeks (Arm 1). MGMT methylated patients received Temozolomide at 75 mg/m2 in addition to Ibrutinib and radiation (Arm 2). Starting dose of Ibrutinib (level 1) was 420 mg daily, level 2 dose was 560 mg daily and dose level -1 was 280 mg. Patients received adjuvant Ibrutinib (Arm 1) and ibrutinib and temozolomide (Arm 2). The primary endpoint included the maximum tolerated dose (MTD) of Ibrutinib with radiation (Arm 1), and ibrutinib, radiation, and temozolomide (Arm 2). Progression-free survival and overall survival are secondary endpoints. RESULTS 27 patients (15 males, 12 females), with a median age of 63 years (range, 34-77 years) were treated on two arms. Dose Limiting toxicity (DLT) in Arm 1 included grade 3 weakness, grade 4 transaminases, and grade 4 neutropenia. DLT in Arm 2 included grade 3 rash, grade 3 transaminases, grade 4 neutropenia, and thrombocytopenia. Ibrutinib was too toxic with radiation in Arm 1, MTD of 420 mg ibrutinib was confirmed in Arm 2. CONCLUSION MTD of Ibrutinib is 420 mg daily with Temozolomide and radiation. Efficacy outcomes (PFS and OS) will be presented.
RBIO-08. MEMANTINE INCREASES DENDRITIC ARBORIZATION OF IMMATURE NEURONS AFTER IRRADIATION WITH NO EVIDENCE OF DISRUPTION IN THE NORMAL BRAIN FUNCTION
Authors: Georgios Alkis Zisiadis, Carlos Rodrigues, Giussy Pizzirusso, Luis Arroyo-García, Ahmed Osman, Klas Blomgren
Journal: Neuro-Oncology (2022)

Abstract Cranial irradiation (IR) is a cornerstone in the treatment of high-grade pediatric brain tumors. While lifesaving, it is associated with severe sequalae in 50-90 % of the survivors, as they often show disabling cognitive dysfunction, declined IQ, impaired processing speed, anxiety and posttraumatic stress symptoms, resulting in poorer academic accomplishments and social isolation. Memantine (Mem) is a non-competitive NMDA receptor antagonist and a potent enhancer of neural plasticity. While an improvement in cognition in post-IR cancer survivors and in synaptic plasticity in association to hippocampal neurogenesis have been documented, the exact mechanisms underlying Mem’s actions are poorly understood. The goal of this project is to further dissect the actions of Mem and identify factors that contribute to hippocampal neurogenesis. To this end, 20-day-old C57BL6/J mice were subjected to a single dose of 7 Gy whole brain irradiation and then supplied with Mem in the drinking water (10 mg/kg/day) to obtain a steady-state plasma concentration of the drug. Two weeks after IR, Sholl analysis of the morphology of the newborn neurons of Mem treated animals showed a statistically significant increase in coverage area (500 µm2 vs. 250 µm2, p &amp;lt; 0,0001) and number of dendrites (15 vs. 5, p &amp;lt; 0,0001) compared to non-treated individuals. Bulk-RNA sequencing analysis revealed 9 differentially expressed genes (alpha=0.1) between the hippocampal cell populations of Mem and vehicle-treated IR mice, which are related to protein folding and the programmed cell death machinery. At six weeks after IR, Mem treatment maintains the gamma oscillatory dynamics in the hippocampal CA3 region (~2x10-9 V2 in non-IR, ~1x109 V2 in IR), but with no apparent recovery to the sham levels. These results emphasize the strong neurogenic effect that Mem exerts on the surviving newborn neurons, while also highlighting Mem’s low toxicity and impact on the normal function of the brain.
EXTH-89. EXPLORING ANTI-TUMOR EFFECTS OF SMALL MOLECULE INHIBITORS OF CDK4/6, FAK, AND RAF/MEK IN PRECLINICAL MODELS OF MENINGIOMA
Authors: Nazanin Ijad, Katie L Waller, Naema Nayyar, Juliana M Larson, Joshua Spear, Daniel Cahill, Frederick G Barker, Evanthia Galanis, Jann Sarkaria, Hiroaki Wakimoto, Rachael Vaubel, Priscilla Brastianos
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Adequate treatment options are limited for patients with meningiomas once they have exhausted surgery and radiation. As our molecular understanding of meningiomas and their progression has improved, CDK, FAK, and RAF/MEK pathways have emerged as potential avenues for therapeutic intervention. However, patient-derived cell and xenograft models of meningiomas are difficult to establish, presenting a challenge in preclinical testing and validation of new therapeutic targets. The objective of this study is to develop informative preclinical models of meningiomas and use those to evaluate the activity of potent and selective inhibitors of CDK4/6, FAK, and RAF/MEK. METHODS We used CellTiter-Glo assay to assess the anti-tumor effects of CDK4/6 inhibitor abemaciclib, FAK inhibitor defactinib (VS-6063) and dual RAF/MEK inhibitor RO5126766 (VS-6766) in BEN-MEN-1 (WHO Grade I, NF2-mutant), CH157-MN (WHO Unknown, NF2-mutant), and IOMM-Lee (WHO Grade III, CDKN2A loss) cell lines. Additionally, we used CyQUANT assays to quantify anti-proliferation activity of these inhibitors in a newly established patient-derived cell line MN14 (WHO Grade II, NF2 mutant). In parallel, we continue our attempts to establish patient-derived cell and xenograft models using freshly isolated surgical specimens of progressive meningioma. RESULTS Defactinib monotherapy significantly decreased cell viability across a 10nM-10μM range for all three established cell lines. RO5126766 showed improved efficacy (by 10-fold) in IOMM-Lee, compared to CH157-MN and Ben-Men-1. Abemaciclib showed potent effects at 10nM in IOMM-Lee and BEN-MEN-1, compared to 100nM for CH157-MN. In the MN14 patient-derived cell line, established from an NF2-mutant atypical meningioma, we observed a significant decrease in cell proliferation with defactinib. A decrease in cell proliferation was also observed with RO5126766 and abemaciclib. CONCLUSION Selective inhibitors of CDK4/6, FAK, and RAF/MEK showed anti-meningioma activity against traditional and patient-derived cell models in vitro. Molecular characterization and establishment of patient-derived models that encompass the diversity of clinical meningiomas are ongoing.
EXTH-65. SYNERGISTIC ONCOLYTIC EFFECTS OF TEMOZOLOMIDE AND ONCOMAGNETIC THERAPIES IN GLIOBLASTOMA
Authors: Arvind Pandey, Shashank Hambarde, David Baskin, Santosh Helekar
Journal: Neuro-Oncology (2022)

Abstract The noninvasive Oncomagnetic device developed in our laboratory selectively kills glioblastoma (GBM) and other cancer cells while sparing normal developing neurons and astrocytes in vitro. We have reported that brief 2 – 6 h of daily Oncomagnetic brain stimulation causes &amp;gt;30% reduction of contrast-enhanced tumor (CET) volume in an end-stage recurrent GBM patient after a ~30-day treatment. We have evidence that the spinning oscillating magnetic fields (sOMF) generated by this device disrupts electron transport in the mitochondrial respiratory chain, at least in part by inhibiting the activity of Complex II succinate dehydrogenase, leading to a marked increase in reactive oxygen species (ROS) and consequent cancer cell death. Here, we further studied the cellular effects of sOMF treatment alone and in combination with Temozolomide (TMZ) on GBM cell lines with other methods and investigated the response to Oncomagnetic monotherapy (OMT) in a mouse GBM model. We treated LN229 and U87 GBM cells with sOMF with and without a sub-therapeutic dose of TMZ. To study the anticancer effect of sOMF in vivo, we developed syngeneic GBM tumors in BALB/c mice by stereotactic intracranial injection of GL261WT cells. Our results show that cytotoxic effects of sOMF or TMZ alone, as measured by the MTT assay and reduced cell survival, are significantly potentiated by combining the two treatments. OMT of tumor-bearing mice using a whole-body sOMF stimulation method causes substantial retardation of tumor growth and reduction of the CET volume in 9.4 T MRI scans. To study the molecular pathways involved in the treatment response we are mapping alterations in various key biomarkers in treated tumor tissues and comparing them with those in untreated controls. These experiments will unravel the molecular mechanism of action underlying the response to OMT in GBM and help develop a sound rationale for an effective therapeutic protocol.
STEM-18. EPIGENETIC AND MOLECULAR COORDINATION BETWEEN HDAC2 AND SMAD3-SKI IS REQUIRED FOR GROWTH AND STEM CELL CHARACTERISTICS OF BRAIN TUMOUR STEM CELLS
Authors: Ravinder Bahia, Xiaoguang Hao, Rozina Hassam, Orsolya Cseh, Danielle Bozek, H Artee Luchman, Samuel Weiss
Journal: Neuro-Oncology (2022)

Abstract Brain tumour stem cell population in glioblastoma (GBM) display key cancer stem cell characteristics of high self-renewal and drug resistance that are maintained by the coordinated functions of epigenetic and molecular regulators. Yet, specific epigenetic mechanisms that, in collaboration with relevant molecular pathways, help maintain a stem-like state in BTSCs remain poorly understood. Here, we identify HDAC2 as a foremost epigenetic regulator in BTSCs that specifically utilizes the transforming growth factor-β (TGF-β) pathway related proteins, SMAD3-SKI, for remodelling BTSC chromatin accessibility and transcriptional programs to facilitate their stemness and tumorigenic potentials. Our initial drug screening revealed that selective inhibition of HDAC1 and 2 with romidepsin was effective in targeting BTSC viability, cell proliferation and self-renewal in vitro. Using CRISPR-cas9 knockout and shRNA knockdown strategies, we further demonstrated that loss of HDAC2 disrupts an epigenetic and molecular coordination between HDAC2 and SMAD-SKI proteins, which negatively impacts BTSC survival, cell proliferation and self-renewal in vitro and improves median survival in orthotopic xenograft mouse models. Loss of HDAC2 showed reduction in the protein abundance of transcriptional regulator, SMAD3 and negative regulator protein, SKI. However, overexpression of SMAD3 in HDAC2 deficient BTSCs could partially rescues their cell functional deficits. These findings suggest that context-specific epigenetic regulations by HDAC2 and its interaction with the critical transcriptional regulators, SMAD3-SKI, maintains the stemness and growth characteristics of BTSCs. Further HDAC2 overexpression increases cell proliferation and self-renewal abilities in normal neural stem cells (NSCs). These findings thus support the role of HDAC2 as a key epigenetic determinant of stemness in normal NSCs and of cancer stem cell characteristics and tumorigenic potential in BTSCs. Collectively, our data raises the potential that disruption of the coordinated mechanisms regulated by HDAC2-SMAD3-SKI axis may be an effective therapeutic approach for targeting GBM BTSCs.